Radioembolization (RE), referred to as selective internal radiation therapy (SIRT) in older literature, is the intra-arterial delivery of small beads (microspheres) impregnated with yttrium-90 via the hepatic artery. The microspheres, which become permanently embedded, are delivered to tumor preferentially to normal liver, as the hepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic artery for blood supply while normal liver is primarily perfused via the portal vein.

Hepatic tumors can arise either as primary liver cancer or by metastasis to the liver from other tissues or organs. Local therapy for hepatic metastasis is indicated only when there is no extrahepatic disease, which rarely occurs for patients with primary cancers other than colorectal carcinoma (CRC) or certain neuroendocrine malignancies. Local therapy by surgical resection with tumor-free margins or liver transplantation is the only potentially curative treatment. For liver metastases from CRC, randomized trials have reported that post-surgical adjuvant chemotherapy (administered systemically or via the hepatic artery) decreases recurrence rates and increases time to recurrence. Important prognostic factors for survival include site and extent of primary tumor, hepatic tumor burden, and performance status.

Unfortunately, most hepatic tumors are unresectable at diagnosis, due either to their anatomic location, size, number of lesions, concurrent nonmalignant liver disease, or insufficient hepatic reserve. Palliative chemotherapy by combined systemic and hepatic artery infusion (HAI) may increase disease-free intervals for patients with unresectable hepatic metastases from CRC. However, durable responses to chemotherapy are less likely for patients with unresectable primary hepatocellular cancer (HCC).

The use of external beam radiotherapy (EBRT) and the application of more advanced radiotherapy approaches (eg, intensity-modulated radiotherapy [IMRT]) may be of limited use in patients with diffuse, multiple lesions due to the low tolerance of normal liver to radiation compared with the higher doses of radiation needed to kill the tumor.

Various non-surgical ablative techniques have been investigated that seek to cure or palliate unresectable hepatic tumors by improving loco-regional control. These techniques rely on extreme temperature changes (cryosurgery or radiofrequency ablation [RFA]), particle and wave physics (microwave or laser ablation), or arterial embolization therapy including chemoembolization, bland embolization, or RE.

Radioembolization (RE), referred to as selective internal radiation therapy or SIRT in older literature, relies on targeted delivery of small beads (microspheres) impregnated with yttrium-90 (90Y). The rationale for radioembolization is based on the following: 1) the liver parenchyma is sensitive to radiation; 2) the hepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic artery for blood supply while normal liver is primarily perfused via the portal vein; and 3) 90Y is a pure beta emitter with a relatively limited effective range and short half-life that helps focus the radiation and minimize its spread. Candidates for radioembolization are initially examined by hepatic angiogram to identify and map the hepatic arterial system, and at that time, a mixture of albumin particles is delivered via the hepatic artery to simulate microspheres. After, single-photon emission computed tomography (SPECT) gamma imaging is used to detect possible shunting of the albumin particles into gastrointestinal or pulmonary vasculature.

Currently 2 commercial forms of 90Y microspheres are available: a glass sphere, TheraSphere® (MDS Nordion Inc., Ontario, Canada) and a resin sphere, SIR-Spheres® (Sirtex Medical Limited; Lake Forest, IL). Non-commercial forms are used mostly outside the United States. While the commercial products use the same radioisotope (90Y) and have the same target dose (100 Gy), they differ in microsphere size profile, base material (i.e., resin versus glass) and size of commercially available doses. The physical characteristics of the active and inactive ingredients affect the flow of microspheres during injection, their retention at the tumor site, spread outside the therapeutic target region, and dosimetry calculations. Note also that the U.S. Food and Drug Administration (FDA) granted premarket approval of SIR-Spheres®, for use in combination with 5-floxuridine (5-FUDR) chemotherapy by HAI, to treat unresectable hepatic metastases from colorectal cancer. In contrast, TheraSphere® were approved by humanitarian device exemption for use as monotherapy to treat unresectable HCC. In January 2007, this HDE was expanded to include patients with hepatocellular carcinoma who have partial or branch portal vein thrombosis. For these reasons, results obtained with one product do not necessarily apply to other commercial (or non-commercial) products.

Unresectable primary hepatocellular carcinoma (HCC)

The majority of patients with HCC present with unresectable disease and treatment options are limited secondary to the chemoresistance of HCC and the intolerance of normal liver parenchyma to tumorcidal radiation doses. Results of 2 randomized controlled trials have shown a survival benefit using transarterial chemoembolization (TACE) therapy versus supportive care in patients with unresectable HCC. In one study, patients were randomized to TACE, TAE (transarterial embolization) or supportive care. One year survival rates for TACE, TAE and supportive care were 82%, 75% and 63%, respectively and two year survival rates were 63%, 50% and 27%, respectively. A recent multicenter, randomized, double-blind placebo controlled phase 3 trial that enrolled 602 patients with advanced HCC randomly assigned patients to receive sorafenib versus placebo. Overall survival (OS) was significantly longer in the sorafenib group compared with placebo (10.7 versus 7.9 months), respectively; hazard ratio for sorafenib, 0.69 (p<.001).

Unresectable intrahepatic cholangiocarcinoma

Cholangiocarcinomas are tumors that arise from the epithelium of the bile duct and are separated into intrahepatic and extrahepatic types. Intrahepatic cholangiocarcinomas appear in the hepatic parenchyma and are also known as peripheral cholangiocarcinomas. Resection is the only treatment with the potential for cure, and 5-year survival rates have been in the range of 20% to 43%. Patients with unresectable disease may select among fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyridimine chemoradiation or best supportive care.

Unresectable metastatic colorectal carcinoma (CRC)

Fifty to sixty percent of patients with colorectal cancer will develop metastases, either synchronously or metachronously. Select patients with liver only metastases that are surgically resectable can be cured, with some reports showing 5-year survival rates exceeding 50%. Emphasis on treating these patients with potentially curable disease is on complete removal of all tumor with negative surgical margins. The majority of patients diagnosed with metastatic colorectal disease are initially classified as having unresectable disease. In patients with metastatic disease limited to the liver, preoperative chemotherapy is sometimes used in an attempt to downsize the metastases to convert the metastatic lesions to a resectable status (conversion chemotherapy).

In patients with unresectable disease that cannot be converted to resectable disease, the primary treatment goal is palliative, with survival benefit shown with both second and third-line systemic chemotherapy. Recent advances in chemotherapy, including oxaliplatin, irinotecan and targeted antibodies like cituximab, have doubled the median survival in this population from less than a year to more than two years. Palliative chemotherapy by combined systemic and hepatic artery infusion (HAI) may increase disease-free intervals for patients with unresectable hepatic metastases from CRC.

Radiofrequency ablation (RFA) has been shown to be inferior to resection in local recurrence rates and 5-year overall survival, and is generally reserved for patients with potentially resectable disease that cannot be completely resected due to patient comorbidities, location of metastases (i.e., adjacent to a major vessel) or an estimate of inadequate liver reserve following resection. RFA is generally recommended to be used with the goal of complete resection with curative intent. The role of local (liver-directed) therapy (including radioembolization, chemoembolization and conformal radiation therapy) in debulking unresectable metastatic disease remains controversial.

Unresectable metastatic neuroendocrine tumors (NET)

Neuroendocrine tumors are an uncommon, heterogeneous group of mostly slow-growing, hormone-secreting malignancies, with the average patient age being 60 years old. Primary NETs vary in location, but most are either carcinoids (which most commonly arise in the midgut) or pancreatic islet cells. Carcinoid tumors, particularly if they metastasize to the liver, can result in excessive vasoactive amine secretion including serotonin and are commonly associated with the carcinoid syndrome (diarrhea, flush, bronchoconstriction and right valvular heart failure).

Although they are considered to be indolent tumors, at the time of diagnosis, up to 75% of patients have liver metastases, and with metastases to the liver, 5-year survival rates are <20%. Surgical resection of the metastases is considered the only curative option; however, less than 10% of patients are eligible for resection, as most patients have diffuse, multiple lesions.

Conventional therapy is largely considered to be palliative supportive care, to control, eradicate or debulk hepatic metastases, often to palliate carcinoid syndrome or local pain from liver capsular stretching. Therapies for unresectable metastatic NET include medical (somatostatin analogues like octreotide), systemic chemotherapy, ablation (radiofrequency or cryotherapy), transcatheter arterial embolization (TAE) or chemoembolization (TACE), or radiation. Although patients often achieve symptom relief with octreotide, the disease eventually becomes refractory, with a median duration of symptom relief of about 13 months, with no known effect on survival. Systemic chemotherapy for these tumors has shown modest response rates of limited duration, is better for pancreatic NETs compared to carcinoids and is frequently associated with significant toxicity. Chemoembolization has shown response rates of almost 80%, but the effect is of short duration and a survival benefit has not been demonstrated.

Miscellaneous metastatic tumors

Small case reports have been published on the use of RE in many other types of cancer with metastases, including breast, head and neck (including parotid gland), pancreaticobiliary, anal, thymic, thyroid, endometrial, lung, kidney, gastric, small bowel, esophageal, ovarian, cervical, prostatic, bladder and for melanoma, sarcoma and lymphoma.

Radioembolization may be considered medically necessary to treat primary hepatocellular carcinoma that is unresectable and limited to the liver.

Radioembolization may be considered medically necessary in primary hepatocellular carcinoma as a bridge to liver transplantation.

Radioembolization may be considered medically necessary to treat hepatic metastases from neuroendocrine tumors (carcinoid and noncarcinoid) with diffuse and symptomatic disease when systemic therapy has failed to control symptoms.

Radioembolization may be considered medically necessary to treat unresectable hepatic metastases from colorectal carcinoma that are both progressive and diffuse, in patients with liver-dominant disease who are refractory to chemotherapy or are not candidates for chemotherapy.

Radioembolization is considered investigational for all other hepatic metastases except as noted above.

Radioembolization is considered investigational to treat primary intrahepatic cholangiocarcinoma.

Radioembolization is considered investigational for all other indications not described above.

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

09/03/2010: Changed "Selective Internal Radiation Therapy" to "Radioembolization" in the title and throughout policy. Policy statement re-written to indicate that selective cases of hepatocellular carcinoma and metastatic neuroendocrine tumors may be considered medically necessary. Code Reference section changed from non-covered to covered. Added ICD-9 codes 155.0-155.2, 197.7, and 209.72 as covered diagnoses.

06/21/2011: Deleted the following policy statement: Radioembolization is considered investigational to treat unresectable hepatic metastases from colorectal carcinoma. Added a policy statement to indicate that radioembolization may be considered medically necessary to treat unresectable hepatic metastases from colorectal carcinoma that are both progressive and diffuse in patients with liver-dominant disease who are refractory to chemotherapy or are not candidates for chemotherapy.

04/26/2012: Policy reviewed; no changes.

08/09/2013: Added policy statement to indicate that radioembolization is considered investigational to treat primary intrahepatic cholangiocarcinoma.

04/29/2014: Policy reviewed; description updated. Added information regarding unresectable intrahepatic cholangiocarcinoma to the policy description. Added a policy statement to indicate that radioembolization is consideredinvestigational for all other indications not described.